Temozolomide (TMZ) is an imidazotetrazine derivative that exhibits anti tumor activity. TMZ's activity in vivo is attributed to its potent methylating activity. TMZ is available under the brand name TEMODAR in the form of capsules containing 5 mg, 20 mg, 100 mg or 250 mg of TMZ. TMZ is indicated in the treatment of refractory anaplastic astrocytoma, a form of brain tumour, glioblastoma multiforme and metastatic melanoma.
TMZ is the abbreviation for a compound having the chemical structure 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]1,2,3,5-tetrazine-8-carboxamide or 3-methyl-8-amino carbonyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one. It has the following structure.

U.S. Pat. No. 5,260,291, the entirety of which is incorporated herein by reference, describes TMZ and its derivatives. Also described is a process for the preparation of TMZ and its derivatives involving condensation of 5-diazo-5H-imidazole-4 carboxamide (and related compounds) with isocyanates. However, the process described is very slow, involving reaction times of up to 3 weeks. The process described is also hazardous as it involves handling isocyanates, particularly methyl isocyanate (MIC) either in the gaseous or liquid state.
In general, isocyanates are harmful to animals: they are toxic and exposure is known to cause asthma in humans. In particular, methyl isocyanate (MIC) has the structure CH3—N═C═O and is a volatile (Bp=39.1° C.) colourless liquid. MIC is extremely toxic to animal life and can cause damage by inhalation, contact and ingestion even at concentrations as low as 0.4 ppm.
Due to its relatively low boiling point, MIC vaporises easily which can lead to escape of this reagent into the environment, where it can damage animal life. MIC in the liquid state polymerises readily in an exothermic reaction. When traces of acids, bases or metals are present, the polymerization can occur in an explosive way. These factors combine to make isocyanates, particularly MIC, very difficult to handle safely, particularly on an industrial scale.
US 2007/0225496, the entirety of which is incorporated herein by reference, describes a process for the preparation of TMZ comprising pyrrolysing N′-Methyl-N,N-diphenyl urea to form MIC vapour and slowly condensing the MIC vapour into a reservoir of a solution of 5-diazo-5H-imidazole-4-carboxamide in dimethyl sulphoxide (DMSO). A yield of crude temozolomide of 68.6% is reported. During filtration of the crude temozolomide produced in this process, excess MIC vapors may be released to the atmosphere.
It has now surprisingly been found that the compounds described in U.S. Pat. No. 5,260,291 can be prepared by a new process developed under the present invention that avoids many of the problems encountered in the prior art. The US 2007/0225496 patent describes the process for the preparation of TMZ comprises of pyrrolysing N′-Methyl-N,N-diphenyl urea to form MIC vapour which slowly condenses the MIC vapour into a reservoir of a solution of 5-diazo-5H-imidazole-4-carboxamide in dimethyl sulphoxide (DMSO) whereby excess of MIC vapors may be released to the atmosphere. The inventors of the present invention have worked around curbing the MIC vapors in the atmosphere and have come out with a unique process whereby TMZ is prepared by using a reservoir of a solution of an isocyanate, particularly MIC, in a solvent followed by subsequent addition of 5-diazo-5H-imidazole-4-carboxamide, or a derivative thereof. By the present process MIC vapors are not released in the atmosphere, in fact they are absorbed into a solvent. The present process is thus found to be more industrially feasible as compared to the conventional processes for the preparation of TMZ.
The process of the present invention enables a faster reaction, an improvement in yield and/or an improved purity of the TMZ derivative produced. Further, the process of the present invention allows any excess isocyanate to be destroyed in situ with aqueous acid, thus minimising the risk of release of isocyanate to the atmosphere.